Thursday, December 6, 2012

Is it Time to Re-write the Textbooks on Insulin and Obesity?

A recent study in Cell Metabolism by Dr. Arya Mehran and colleagues found a result that, according to a press release, "could overturn widely accepted notions about healthy eating habits" (1), and has set the Internet abuzz.

In this study, researchers generated mice that lack one copy of the pancreatic insulin gene, and compared them to mice carrying both copies (2). Then, they exposed both groups to a fattening diet, and found that mice lacking one copy of the insulin gene secreted less insulin than the comparison group (i.e., they did not develop the same degree of hyperinsulinemia). These mice were also completely resistant to fat gain, while the comparison group became obese. The authors came to some rather large conclusions based on these results, suggesting that the "accepted model" that hyperinsulinemia is the result of obesity is "incompatible with our results that put the insulin hypersecretion genetically upstream of obesity". Ergo, diet causes hyperinsulinemia, which causes fat gain. It's a familiar argument to those who frequent Internet diet-health circles, except in this case the hyperinsulinemia is caused by a high-fat diet.

The problem is that the "accepted model" they want to replace overnight didn't come out of thin air-- it emerged from a large body of research, which was almost completely ignored by the authors. When carefully considered, this evidence suggests an alternative explanation for the results of Dr. Mehran and colleagues.

In a landmark paper published in the journal Nature in 1997, Dr. Teoman Uysal and colleagues studied a mouse line lacking the inflammatory gene TNF-alpha (3). Due to a suppression of inflammatory signaling, these animals do not develop insulin resistance when placed on a fattening diet. As a result, they do not develop hyperinsulinemia at all-- insulin levels remain the same as lean controls fed a normal diet. This suggests that the hyperinsulinemia of obesity is indeed a compensatory response to insulin resistance. Get rid of insulin resistance, and you get rid of hyperinsulinemia. Meanwhile, in the comparison group fed the same fattening diet, fasting insulin increased by five-fold. Yet despite these huge differences in fasting insulin, both groups of mice developed "marked obesity". Here are the relevant figures:

The same thing was reported for the iNOS knockout mouse, which also does not develop insulin resistance for a similar reason (4). In that case, the mice with normal insulin actually became fatter than the hyperinsulinemic comparison group, but both groups gained fat. The finding that obesity does not depend on hyperinsulinemia has been replicated multiple times in other animal models that do not develop insulin resistance on fattening diets (5, 6). It is unfortunate that Dr. Mehran and colleagues did not cite these papers or attempt to reconcile them with their own findings.

Roughly 20% of obese humans are insulin sensitive and have normal circulating insulin levels, an issue I discussed in my 2012 AHS talk (7). Consistent with the evidence in animal models I just discussed, this demonstrates that hyperinsulinemia is not required for obesity in humans. If the interpretation of Dr. Mehran and colleagues were correct, this should be impossible or at least very rare. Observational studies in humans overall have found that elevated insulin levels do not predict future fat gain (8), offering further evidence against the idea that hyperinsulinemia is required for obesity. Since there have been a lot of studies, they can be cherry picked, but if you consider them as a whole, the majority of studies that found an association actually reported that higher insulin predicts less fat gain over time (8).

Well, where do we go from here? We can either stand on opposite sides of the line and shout at one another, or we can try to put the pieces together into a cohesive framework that explains ALL the evidence. Luckily, such a framework exists and it's pretty simple.

The elevated insulin levels that accompany obesity are a compensatory response to insulin resistance-- this is clear from the papers I cited above, among many others. Therefore, when insulin resistance develops, insulin secretion goes up in parallel, maintaining approximately the same relationship between insulin secretion and insulin sensitivity, so that relatively normal metabolic control is maintained (if this didn't happen, life-threatening metabolic havoc would rapidly ensue, e.g. diabetes or hypoglycemia). This explains why suppressing insulin resistance and hyperinsulinemia in parallel has little or no impact on fat gain. In that case, total insulin action on fat tissue (i.e., the normal relationship between insulin secretion and insulin sensitivity) is preserved.

However, when you uncouple insulin secretion from insulin sensitivity, you change the normal balance between the two, and you can affect fat mass. That's why the fat-specific insulin receptor knockout mouse is resistant to obesity (9). It's also one of the reasons why people lose fat when they develop diabetes, which is a (relative or absolute) deficiency of insulin action. Correcting the insulin deficiency of diabetes frequently causes fat gain for the same reason. In the paper by Dr. Mehran and colleagues, they suppressed insulin secretion without increasing insulin sensitivity, creating an insulin deficiency state similar to mild diabetes, and the result was the same: elevated blood glucose and resistance to fat gain. I fail to see why this is earth shattering.

Although the result is interesting from an academic perspective, it isn't relevant to common obesity where insulin resistance and insulin secretion parallel one another, and it certainly does not erase all previous evidence suggesting that hyperinsulinemia isn't required for obesity in mice or humans. I think we can hold off on re-writing those textbooks for the time being.

66 comments:

I have a dream, a dream about a day when obesity researchers will feed normal animals the real food that people eat according to the different ways they can choose to do this.The Atkins mice will run mazes against the Ornish mice; the SAD mice, the USDA mice, the PHD mice, the Mediterranean Diet mice will all compete. Each dietary advocate can sponsor and supply their own team of mice; better still, use an animal that can fight or race as well as sit on the scales.And if there's no clear-cut winner, it'll be time to decide that mice were always a poor model for this sort of thing.

Very true. We need to study more animals that seem to live a long time for their size (like us). I wonder what happens to a naked mole rat on different diets -- I bet it doesn't really very much from its programmed longevity.

I read this paper yesterday and couldn't see any way to avoid the conclusion that in this model, the insulin is indeed causing the obesity. But apparently it can only do it in the context of a high fat diet. So now it's fat and not carbohydrate that causes hyperinsulinemia and obesity.

1. "People" don't lose fat when they develop diabetes. That's only type 1 or very advanced type 2 in which insulin production is close to zero, so almost no glucose can get into cells and they're in essence starving.

2. "Consistent with the evidence in animal models I just discussed, this demonstrates that hyperinsulinemia is not required for obesity in humans." Not required doesn't mean the same as has no effect. People with huge appetites won't gain weight in a metabolic ward where they have access to only 600 calories a day. That doesn't mean appetite doesn't affect weight.

3. There's no reason you can't have a vicious circle. For example, high insulin causes fat gain and increased fat causes IR, which causes high insulin. At each step, the results could be small and only measurable long term.

Therefore you could prove both ways, and depending on preconceived notions, a person's experiments could emphasize one or the other.

Stephan, What I found interesting about this study was the ability to unlink brain insulin from pancreatic insulin.

We know that insulin stimulates the storage of fat through multiple enzyme systems. We also know that insulin in the brain reduces appetite. And we know that the insulin gene can be regulated by epigenetic methylation.

Mice have two insulin genes, Ins1 and Ins2, but humans have only one INS gene, so we can't easily uncouple them. But they might be expressed differently in brain and pancreas. Imagine the following scenarios.

A healthy person eats carbs, insulin levels go up, and more fat is stored. But at about the same time, brain insulin goes up, appetite is decreased, and less is eaten at the next meal or snack, so the extra fat is burned off. This person could thrive and stay thin on a high-carb diet

But someone else might have the brain insulin turned down. There could be many causes: inhibition of the gene, faulty insulin transport into brain, faulty insulin action in brain.

So this person would eat carbs and stimulate fat storage without decreasing appetite, and obesity would result if there were easy access to excess food.

This is consistent with study that shows that people without metabolic syndrome lose weight equally well on any diet, but people with MetS do better with a LC diet.

I think both sides in this controversy are right, and this mouse study may help us solve the puzzle.

I think the gist of Stephan's argument is that insulin is, of course, involved in fat storage. It is involved as a *proximal* cause- in that it is necessary for regulating energy balance.

IMO, the fact that it is a *proximal* cause has duped some otherwise intelligent folks (Taubes, Dobromylskyj) into making "insulin dysregulation" *the root cause* of obesity (the essence of the CIH).

This is clearly not true, and therefore the CIH is falsified. Leptin is the main hormone regulating body fat storage. Sure IR and inflammation are interesting and important processes for metabolic health- but this is not a situation where "both sides are right".

"That's only type 1 or very advanced type 2 in which insulin production is close to zero, so almost no glucose can get into cells and they're in essence starving."

It is a common misconception that "glucose can't get into cells" and that cells are "starving" in type 1 diabetes. However, this is not true. Insulin is not required for glucose uptake; it only enhances it. In fact, glucose uptake in cells increases in an uncontrolled type 1 diabetic; this has been demonstrated with metabolic tracer studies. The reason blood glucose climbs so high in an uncontrolled diabetic is due to runaway gluconeogenesis by the liver.

You said "'People' don't lose fat when they develop diabetes. That's only type 1 or very advanced type 2 in which insulin production is close to zero, so almost no glucose can get into cells and they're in essence starving".

People with type 2 diabetes are leaner than they would otherwise be if insulin secretion could keep up with insulin resistance. The longer they are in an uncontrolled diabetic state, the more weight they will typically lose, even if insulin secretion is not "close to zero". However, despite losing weight, they are not usually lean because in most cases obesity is what got them to diabetes in the first place, and most of them end up being treated.

The fact that T2DM is a state of deficient insulin action on adipocytes is evident in the fact that they have elevated free fatty acids.

I think you've grasped the crux of the matter. There are still some scenarios besides diabetes where insulin signaling could be involved in fat gain (or loss), but it is unlikely to be a major cause of common obesity on a population level.

Uncontrolled diabetes is when a person has diabetic blood glucose and is not on exogenous insulin or other blood glucose lowering therapy. It does not have to be severe diabetes.

You said "if this statement were true, then injecting insulin into a person with IR would make them lose weight."

I don't understand your reasoning there. Diabetics are by definition insulin deficient, and therefore they typically have poorly controlled lipolysis, as evidenced by their elevated FFA. Give them insulin and this corrects the insulin deficiency, corrects poorly controlled lipolysis, and therefore they gain fat.

>The only controversy is whether IR in different tissues>happens at different times.

I agree, I think that’s an interesting question. I’m still looking for an answer.

As I understand it, for adipocytes, different levels of resistance should affect different pathways. For example you don’t need much insulin to stop lipolysis compared to the amount needed to stimulate glucose uptake in the same tissue. So I guess mild adipose IR doesn’t affect the function of insulin to inhibit lipolysis, but definitely stops glucose uptake.

According to a review article (www.ncbi.nlm.nih.gov/pubmed/12080441) IR starts in adipose tissue. But does this mean that adipose tissue is more resistant compared to the muscle cells?

Mice don't normally get fructose in their diet unless they are lab animals.

Try again.

@ jane You don't have to eat fats to have a lot of fat to work with - well known that fructose will spike the Trygly FFA and particularly 16:0

You will get some of the same with just carbs.

Diets that we have evolved to eat would give us trygly around 50 and PP BG under 110.

I'm suspicious of a long term effect of the increase in 18:2 ω-6 linoleic acid in the average US diet being a possible causative agent ( a long term effect - I've seen the short term studies ) of the T2D pandemic.

thanks for the good work. This reminds me of the popular online myth espoused by cholesterol denialists. The idea that inflammation has a role in the pathogenesis of artery disease independent of elevated LDL-C cholesterol. This is just plain nonsense. It does not happen on humans(1) nor in laboratory animals. In fact, you could highlight some of these mechanism studies in the future in order to guide your readers to make choices that support healthy longevity. These are what I have in my mind,as reported by Steinberg, 2008(2):

"Striking evidence of the reversibility of atheroslerotic lesions has been seen in mouse models. Desurmont et al. showed that the hypercholesterolemia in apolipoprotein E–null mice crossed into immunodeficient (nude) mice can be rapidly corrected by introducing the human apolipoprotein E gene via an adenoviral vector. The plasma cholesterol level returned to almost normal within a week or 2, from 400 down to 100 mg/dL, and because no immune response occurred, it stayed down for at least 100 days. Lesion size in the proximal aorta at 17 weeks, which is when the adenoviral vector was injected, was ≈105 μm2; over the next 28 weeks, in the controls (LacZ vector), it further increased 6-fold. However, in the mice receiving the apolipoprotein E vector, lesion size decreased by almost 90%. Moreover, there was a virtual disappearance of foam cells and cholesterol from the lesions and reendothelialization of the aorta".

What Steiberg (2008) is sayin' in essence is that atherosclerosis can be turned on and off as a function of cholesterol in the serum by manipulating the cholesterol metabolism of the mice.

Steinberg continues:

"Reis and colleagues have shown equally dramatic regression in mice. They devised a technique for transplanting a lesion-containing thoracic aortic graft from a hypercholesterolemic apolipoprotein E–null mouse into either a syngeneic normocholesterolemic wild-type recipient or another syngeneic hypercholesterolemic apolipoprotein E–null recipient. This allowed the investigators to suddenly change the environment in which the aortic lesion finds itself to whatever the recipient blood offers. In this study, the donors had been on a Western-type diet for a full 9 months, so they had advanced, complicated lesions containing foam cells, intimal smooth muscle cells, extracellular matrix, and lipid pools. Nine weeks after transplantation into normocholesterolemic recipients, atherosclerotic changes had all but disappeared; in contrast, after 9 weeks in the hypercholesterolemic apolipoprotein E–null recipient, the lesions had increased further in size".

Steinberg is saying that we can transplant a heavily atherosclerotic aorta to healthy mice with low cholesterol levels and simply observe how the aorta heals very rapidly. However, this healing does not occur when the aorta is transplanted to a mice with high cholesterol levels in the serum.

The show escalates:

"Armstrong et al and Armstrong and Megan showed that in cholesterol-fed nonhuman primates, virtually total regression could ultimately be achieved, but it took 40 months after return to a cholesterol-free diet to undo the damage done during 17 months of prior cholesterol feeding.The remarkable thing about these studies is that not only was almost all of the lipid gone from the arteries but also virtually all signs of the inflammatory process were gone. The remains of the lesions were basically scar tissue with no signs of cellular infiltrates.In other words, it appeared that in the absence of continuing hypercholesterolemia, the inflammatory process was not self-sustaining. Simply arresting the hypercholesterolemia by reverting to a normal monkey chow diet caused virtually complete lesion regression without the need for intervention directed specifically at the inflammatory process, results recently confirmed in an elegant series of studies in rabbits"

Above, Steinberg notes that when elevatated cholesterol levels are being lowered, all signs of inflammation dissapear. Thus it looks like, inflammation is simple provoked by elevated LDL cholesterol itself.

"Finally, we have an impressive cascade of experiments showing that returning cholesterol-fed rabbits to a chow diet—and thus lowering their blood cholesterol without pharmacological intervention—markedly reduced many proinflammatory processes associated with lesion progression".

"Taken together, all of these findings suggest that the inflammation associated with atherogenesis is not sufficient in itself to cause further lesion progression or even to maintain lesions at a steady state once the hypercholesterolemia has been fully corrected. In other words, many (or even most) of the inflammatory processes in the advancing lesion are downstream responses ultimately traceable to hyperlipidemia and its consequences".

@karl'..You don't have to eat fats to have a lot of fat to work with - well known that fructose will spike the Trygly FFA..'

Yes, that's true. It all seems to work at least in part by inducing mineral deficiencies. High fructose feeding causes copper deficiency in lab animals, and so does a high-fat diet. How far this is due to changes in gut bacteria, and how far to effects on metal transporters, remains to be seen. Here's a paper showing that fructose feeding reduces expression of the copper transporter Ctr1 in rats.

'..I'm suspicious of a long term effect of the increase in 18:2 ω-6 linoleic acid in the average US diet being a possible causative agent .. of the T2D pandemic.'

So am I. I think mineral deficiencies are a far more promising line of inquiry. Have you seen this post of Stephan's about insulin sensitivity and magnesium?http://wholehealthsource.blogspot.co.uk/2010/02/magnesium-and-insulin-sensitivity.html

When it comes to such complex systems as the human body, I doubt there could be a single root cause for a problem like obesity. I know Gary Taubes (among others) tends to see the argument that obesity is multi-factorial as an excuse to do bad science. But even though much of what the average layperson knows about obesity and how to deal with it is inadequate and often based on bad science, that does not mean the problem of obesity can be reduced to one root cause. Reducing complex problems to the most simple explanation works better in math and physics; it does not work so well with human biology. Perhaps the best chance for success in treating obesity is to address the problem from many angles at once - diet, exercise, stress management, improved sleep, treatment of deficiencies, treatment of emotional problems, etc. Everybody wants a silver bullet, but there are very few of those!

Stephen wrote " It is unfortunate that Dr. Mehran and colleagues did not cite these papers or attempt to reconcile them with their own findings."

This is the big thing.

It has been an absolute disappoinment to notice as how both the establishment and low-carb-proponents (or any other 'camp') consistenty fail to cite papers and emerging evidence which do not conform their agenda and world view. It's resembles what has been going on in Wall Street banks. Bad selfish science. Is it all about fame and money, don't these guys really care about what is right and truthful?

Imo Gretchen has a point. In the diagram on page 726 it can be seen that for *all* experimental animals the ins2 gene was knocked-out. Because of the brain-blood barrier these animals have no insulin signalling left in their brain as was specifically checked by the authors with Taqman quantitative PCR : no ins1 and no ins2 mRNA in the brain of the knock-out mice.

The authors themselves note on Page 733 that "insulin produced locally in specific brain regions will have potent effects on food intake."

Imo it is not inconceivable that the result is due to diminished insulin signalling in the brain. Even more so because the authors themselves note that the effect might be due to 1) more physical activity (driven by hypothalamic signalling) and 2) more activity in brown adipose tissue (The innervation of brown adipose tissue regulates uncoupling and non-shivering heat)

I'm new to the debate on carbs etc. Our paper is about insulin, at the biochemical level. I'm delighted that people are interested in the paper, but it only addresses what it addresses. We don't discuss different diets because we only compared a control diet (20% fat, 50% carb) with a completely unmatched hyperinsulemic diet (58% fat, 25% carb). The goal was to test, for the first time, whether insulin itself, in the absence of insulin resistance or hyperglycemia. And no, hyperinsulinemia and insulin resistance are not the same thing. Connected, but easily uncoupled.

Insulin still gets into the brain. What they did is get rid of local insulin production (though it is controversial that it is produced locally in the brain at all). But it still acts on the hypothalamus via the circulation.

Hi JJ,

Thanks for stopping by. What do you think of the previous papers showing that obesity develops readily in the absence of hyperinsulinemia if the hyperinsulinemia is suppressed by preventing insulin resistance?

Anyways, buddy. Sorry for the off-topic bursts :) This one will be my last for the time being.

@Karl,

you are little behind your times. The causal relationship of LDL-C cholesterol to CHD was largely established already back in the 1970s. REVERSA-mices clearly demonstrate that atherosclerosis can be turned on and off as a plain function of serum cholesterol. The fact that the mices were engineered to be susceptible to CHD is irrelevant. LDL-C is not merely a risk-factor but actually the underlying causal factor influencing CHD. This has been demonstrated literally in thousands of human studies.

Stephen's colleagues on the front-line know what they are talking about:

"Low-density lipoprotein cholesterol (LDL-C) is identified in the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) report as the most abundant and clearly causal atherogenic lipoprotein on the basis of many observational and experimental studies over several decades.1 Guidelines from the American Association of Clinical Endocrinologists (AACE) are in agreement with NCEP ATP III that LDL-C is central in the diagnosis of dyslipidemia. Any LDL-C level above 100 mg/dL appears to promote atherogenesis.1"http://www.lipidu.com/Pillars.aspx?PillarID=2&ChildID=2

Why would you want to have oxLDL constant and stop there when oxLDL modification process is just one form of modification process that causes fatty streak lesions.

Here is an interview with Steinberg

Passwater:Is it accurate to say that only oxidized-LDL starts the plaque process?

Steinberg: No, it seems to me very likely that other modified forms of LDL are involved in plaque formation. What we know so far is that the use of antioxidants can decrease the rate of progression of lesions by 50-80%. That would speak to a major involvement of oxidation, but other things can also lead to foam cell formation. Studies by Dr. John C. Khoo in my laboratory have shown that aggregation of LDL with itself markedly increases the rate of uptake by macrophages. [15] The uptake in that case occurs by way of the native LDL receptor, not the acetyl LDL receptor or oxidized LDL receptor.

Studies by Drs. J. S. Frank and A. M. Fogelman at UCLA have demonstrated the generation LDL aggregates in the subendothelial space. [16] Aggregation does not depend upon prior oxidative modification. So here is a quite distinct mechanism by which LDL uptake into the macrophages can be accelerated and can perhaps initiate the fatty streak lesion.

Studies by Dr. Joseph L. Witztum and others in our laboratory have shown that minor modifications in the structure of LDL can render it immunogenic. Autoantibodies against oxidized LDL have been demonstrated in rabbits and in humans as well. Therefore, a complex of a modified LDL particle and an antibody against it can be taken up into macrophages by way of a completely different receptor, the receptor for immunoglobulins (the FC receptor).

So, there are at least two or three alternative modifications of LDL that could account for foam cell formation. These have not yet been studied in vivo as intensively as oxidative modification, and so we are not in a position to say with any confidence how important they may be.http://www.healthy.net/scr/interview.aspx?Id=197

Peter It's you and not Karl who are behind the times. Healthy Longevity and I have been having a discussion about this. John Khoo's work, mentioned in the interview you quoted, shows that LDL aggregates if its hydrophobic core is exposed. Oxidation is not the only way LDL can be destabilised.

LDL is supposed to prevent atherosclerosis, not to cause it. It carries nutrients of various kinds, including fat-soluble vitamins, to tissues that need them. It's normally kept in good condition by protective factors in HDL, and if HDL doesn't have enough of them because of a rubbish diet, LDL will get damaged and be atherogenic.

off topic from Stephen's insulin theme. I brought this up because just like with insulin we have equally informative mechanism studies in cholesterol research that allow careful cause-and-effect analysis. That's why these animal models are so important in the first place.

Holding other factors constant, as I already referred to, having low LDL-C levels since birth, without altering any other bio markers, due to inherited mutations in 9 different SNPs, confers a risk reduction of around 55% per every 1mmol/l LDL-C lowered. Over 1 million human genotypes studied. Each of the mutations in various SNPs lower LDL-C with a mechanism of its own, however the end result is identical with very little heterogeneity, which suggests that diet and exercise have can have equal benefit to CHD risk as genetic factors. That is, the benefits of low LDL-C will accrue independent of the mechanism used. BTW out of the 9 studied SNPs, one was the statin-targeted HMG-CoA. People with genetic mutations that lower LDL-C levels via HMG-CoA show risk reduction to CHD of equal size as compared to those with inherited mutations in the 8 other SNPs studied. This suggests that the effects of statin on risk of CHD is mediated largely or entirely through effect on circulating levels of LDL, rather than through some other pleiotropic effect.

Moreover, people born with rare condition that cause extremely low LDL-C levels(<15mg/dl) typically live 9-12 longer than their peers. A condition where the amount LDL-C is very little and thus carrying very little "nutrients of various kinds, including fat-soluble vitamins, to tissues that need them" is clearly very beneficial, and the benefits associated with very low circulating LDL-C levels is dependent of magnitude and timing. When LDL-C is lowered by >50% we typically start to see reduction in plaque size even when LDL-C lowering theraphy is started at very late stages of life as several large-scale, double blinded statin studies have shown (mean age at the time of randomization at statin trials is 63).http://circ.ahajournals.org/content/118/6/672.full

Peter, since you're block-quoting some new material, here's a brief rejoinder:

1)" LDL-C is not merely a risk-factor but actually the underlying causal factor influencing CHD. This has been demonstrated literally in thousands of human studies. "

No it hasn't. In order to "demonstrate" such a thing, you'd need a completely randomized intervention trial manipulating LDL-C in isolation from numerous other pathways. This has't been done. Instead, you're relying on a mix of observational and suggestive experimental evidence. This is not bad, in itself, except that there are numerous contradictions in your position, other syntheses may better explain the evidence, and your dogmatic tone belies the certainty you allege to have. {BTW, statin trials don't count, because they certainly do have other effects than lowering LDL.}

2) Steinberg himself is admitting that it is *modified LDL* not LDL in and of itself that initiates the "fatty streak". This contradicts your position. Sure, statistically, if you have less LDL, then *ALL OTHER THINGS CONSTANT* you'll probably have less modified-LDL. The mechanism in this case is residence time, not concentration- and this is a superior synthesis of the evidence coming from LDL receptor mutation studies.

The point is, in terms of diet and lifestyle, focusing on supporting antioxidant systems, resolving inflammation, etc. are all likely to be far more important than a focus on reducing LDL-C. In fact, it's entirely conceivable that interventions raising LDL-C will still dramatically reduce CVD risk (Ron Krauss has pretty well shown this by now).

3) Given initiation of "fatty streaks" by modified-LDL we still have to understand the progression of atherosclerosis, which is likely mediated by immune/infllammation processes more than a "mass effect" of LDL glomming up the arteries.

I cited a randomized trial consisting the genotype of over 1,000 000 participants. Besides, we wouldn't need RCTs for this. We know cigarette smoking is exposure to asbestos is harmful without a single RCT. Scientists are free to use their logic instead of relying online nonsense about prerequisites of RCTs. Atherosclerosis is disease take begins in the childhood and develops during several decades. You can be at war with science or embrace it.

Inflammation is the downstream of elevated cholesterol (including elevated HDL-C) and has no independent role in the pathogenesis of coronary artery disease. This is mainstream biomedical science. None of these identified LDL modification process take place when LDL-C are kept physiological, that is in similar levels that is observed in free-ranging mammalians. Modication process take place when LDL-receptors become saturated, too much of the good stuff, turns bad.

You can choose to troll around and pretend that LDL-C levels +200% to what is biologically normal and what customarily observed in people living Western societies is not harmfull as such. Just have it at that.

"The average total cholesterol level in American adults today is 208 mg/dl (corresponding to an LDL of approximately 130 mg/dl) (13). In this case, average is not normal because atherosclerosis is present in up to 40% to 50% of women and men by age 50 (14).Atherosclerosis is endemic in our population in part because the average person's LDL level is approximately twice the normal physiologic level(Figure 1)".http://content.onlinejacc.org/article.aspx?articleid=1135650

"In contrast to feeding cholesterol and/or saturated fat, it is not possible to produce atherosclerotic plaques in herbivores by raising the blood pressure chronically, by blowing cigarette smoke in their faces for their entire lifetimes, or by somehow raising the blood glucose levels without simultaneously feeding them an atherogenenic diet. Presently, it is commonly stated that “atherosclerosis is an inflammatory disease.” Inflammatory cells, however, are infrequent in plaques of coronary arteries studied at necropsy or in endarterectomy specimens. When present, the few mononuclear cells—even giant cells—appear to be present due to a reaction to the deposits of lipid (pultaceous debris) present in the plaque.“ Inflammation” appears to be a surrogate for elevation of serum C-reactive protein or various cytokines (interleukins 1 and 6, tumor necrosis factor, etc), not for inflammatory cells in plaques. Thus, it is a definition situation, and the morphologic definition of inflammation is not applicable"

In summary, the connection between cholesterol elevation and atherosclerotic plaques is clear and well established. Atherosclerosis is a cholesterol problem! If one has elevated cholesterol, has an elevated blood pressure, smokes cigarettes, or has an elevated blood sugar, these additional factors serve to amplify the cholesterol damage but they by themselves do not produce atherosclerotic plaques! Societies with a high frequency of systemic hypertension or a high frequency of cigarette smoking but low cholesterol levels rarely get atherosclerosis".

"....The lower the LDL cholesterol the better, and this principle has been established repeatedly despite the voices of the anticholesterol, antistatin fallacy mongers! It's the cholesterol, stupid!"

--William Clifford Roberts, American Journal of Cardiology, editor in chief.

"There was little question after the first major statin trials that the reduction in CVD was related to lipid lowering and was totally consistent and supportive of the lipid hypothesis. However, stimulated by funding from the pharmaceutical industry, in which competition was fierce for market share and was driven mainly by the efficacy of lowering LDL-C levels, manufacturers of less-effective agents for lowering LDL-C levels helped propagate “beyond LDL-C” theories; these theories were that statins reduced CVD events by means other than lipid reduction, often termed pleotropic effects, usually shown in in vitro laboratory studies or small, poorly standardized surrogate marker trials. This belief culminated in an RCT by a pharmaceutical company that was designed to show that more LDL-C reduction with a competitor's statin achieved no greater benefit.13 However, the results of that study clearly and convincingly showed otherwise, with additional reduction in CVD events with the drug that lowered LDL-C levels more. Even with this evidence, and perhaps with an even more powerful statin about to be approved, the investigators suggested that the reduced events were due to pleotropic effects of the more efficacious statin. However, the trial was soon followed up with results from another head-to-head RCT, with the same drug at different LDL-C lowering doses,14 which eliminated the pleotropic potential and rein-forced that lower is better"http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2665973/

As Steinberg (2008) notes, the mean age when LDL-C lowering theraphy is iniated is too high presently! Even stabilized plaques can cause events on people with several decade long atherosclerotic burden. "The early, the better"

Evidence Mandating Earlier and More Aggressive Treatment of Hypercholesterolemiahttp://circ.ahajournals.org/content/118/6/672.full

We have tons of elaborated models on insulin, obesity and cholesterol. Stephen are you aware of any (animal)model where CHD has been turned off while simultaneously raising LDL-C cholesterol as Chris Wilson claims Ronald Krauss to have demonstrated? I've never heard of such model? If such model was possible it ought to exist by now. I've heard about tons of models where everything else has been held constant and atherosclerosis is produced and regressed as simple function of cholesterol. Some of these new models where parasites have been able to regress plaques on animals have been very intriguing. Parasitic burdens are very heavy on indigenous populations.

While looking at the preponderance of evidence I cannot but help thinking that for optimal health there's no reason to assume we could successfully pull it off while having LDL-C cholesterol much above to what is observed in free-ranging mammalian species. Having cholesterol above what is biologically normal would be risky. Similarly as having supraphysiologic blood-pressure.

As early as 1970, many of the country's experts in atherosclerosis and preventive cardiology, and the American Heart Association, were already convinced that there was a causal connection between blood cholesterol and coronary heart disease, as discussed in the earlier installments of this series (1–3)" . http://www.jlr.org/content/47/1/1.full

Peter, the Krauss work I referred to was regarding the atherogenicity of different LDL patterns, e.g. http://www.jlr.org/content/43/9/1363.short

Let's be simplistic for a second: Say you have two kinds of LDL (A and B). Type B is observed to infiltrate the endothelium at 8 times the rate as type A (or something like that). Now, let's say that type B is "small, dense" and type A is "large, bouyant". Now, let's say there are a ton of folks running around talking about LDL-C which is a *mass measurement* that does not tell you whether you have type A, type B, or how many of each.

You feed a diet rich in saturated fat and cholesterol, and, say, 80% of the type B particles shift to type A, but the particle count remains constant. LDL-C has gone up, but LDL-p is static, and the atherogenicity has declined several-fold.

The reasonableness of this kind of reasoning (which is certainly over-simplified) has been confirmed in a few studies, e.g.: http://www.ncbi.nlm.nih.gov.lp.hscl.ufl.edu/pubmed/16685042?dopt=Abstract&holding=npg

BTW, I agree with you, that, all other things being equal, it is probably better to have lower LDL-P (particle count) rather than higher! I disagree with your dogmatic insistence that LDL-C (mass count) is the end-all-be-all of CHD.

Bon Voyage! Chris

P.S. Since you clearly are so passionate about this topic, why aren't you trying to become a biomedical researcher?

I'll be quick. I don't have time for this right now. Krauss has a huge work ahead in trying to make the biomedical community to buy his particle size nonsense. He is a merchant of doubt paid by the dairy and beef industry (which does not automatically mean his research has no value, though). Moreover, discordence between LDL-P and LDL-C is observed pretty much solely on people with metabolic syndrome. The seperate assesment of LDL-P informs doctors about the extent and aggressiveness of the LDL-C lowering theraphy to which diabetics are put by default now days, independent of their baseline LDL-C levels. There's no upside having any more than 15mg/dl in the LDL fraction.

"All lipoprotein particles in the LDL fraction are atherogenic, independent of size"

http://www.lipid.org/uploads/300/Expert%20Panel%20Paper.pdf

Scott Grundy, the chaiman of ATP-3 expert panel has a bit different take about the risk assesment in the future. It's not really going in the Krauss way.

Measuring apolipoproteins does not help risk prediction (June 19, 2012)

"Grundy adds that recommendations for statin use in primary prevention may need to be revisited now anyway, highlighted by the recent meta-analysis from the Oxford group that showed benefits of statins in much lower-risk individuals than those for whom treatment is currently advised.And he suggests that risk assessment may in the future move away from measuring many biomarkers and instead focus on subclinical atherosclerosis with imaging methods or simple risk projection based on age, sex, LDL levels, and perhaps another major risk factor".http://www.theheart.org/article/1417589.do

"Only in populations that maintain very low levels of serum cholesterol, e.g., total cholesterol <150 mg/dL (or LDL cholesterol <100mg/dL) throughout life do we find a near-absence of clinical CHD.19,23-28"

@peterCorrelative studies really don't interest me much other than to suggest where a real experiment might be interesting.

If the cholesterol mantra that feeds the grant-money-food-chain was correct, the Look Ahead trail would not have been pulled( those darn body counts again), pumping HDL via drugs would have worked and other drugs besides statins that lower LDL would work. ( Statins block Lox-1 that take up oxLDL and have up to ten other effects other than reducing LDL).

Evolution does not engineer - reuse and competitive needs for the same proteins is the rule not exception. Thus LDL did not evolve to cause CAD - it is a swiss army knife - has several functions including immune functions. Anyone that understands the failure of current medicine to significantly improve the fate of CAD patients realizes that LDL is not simple answer. (many people with significantly elevated LDL just don't get CAD ). If you dig into the modern research you will find continued work on immunological focus - on-going drug tests with interleukin suppressing drugs etc. etc. You will also find that adipose tissue has other functions than storing fat - immune function - secretion of cytokines that drive immunological functions (inappropriately at times ).

It is past time to keep repeating the mantra that CAD is simply a function of LDL.

The connection with BG is that what is considered normal (not average) is not normal - postprandial BG over 110 is a failure. (This failure drives LDL => oxLDL.) We have not (yet?) evolved tolerance to eating the industrial food diet full of sugar and high carb grains and perhaps grain fed flesh.

By the way humans are not mice. They also have not evolved to eat the 20% sucrose in a so-called high-fat diet. Not sure what such experiments show other than a way to keep grant-money flowing.

I don't know even where to begin with you. I am seriously puzzled. What has Look Ahead trial to do with the lipid-theory?

Other drugs besides statins work, and that's why resins (a bile acid sequestrant) were being used. In fact even bypass of the intestine has been used to decrease CAD events. A meta-regression curve accumulated from 108 randomized controlled trials of various medical and dietary based lipid modifying interventions has established that lowering LDL cholesterol significantly decreases the risk of coronary heart disease and all-cause mortality, independent of changes to HDL cholesterol and triglycerides, and non-lipid effects of specific drugshttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2645847/

Most people who smoke do not get lung cancer, yet cigarette's are the causal factor in lung cancer. So, I have really hard time to understand your level of argumentation. Most drunk drivers never crash, it's just that so many do.

Sucrose actually opens up the arteries in animal experiments (monkey). And probably does the same on humans. The sugar-CHD link is very weak. Traditionally cultures in Cuba, Costa Rica, Equador, etc have shown very high sugar consumption, and nevertheless low CHD rates, atleast compared to US.

An update version of the lipid theory is nicely captured in this New York Times article from last May (2012):

Doubt Cast on the ‘Good’ in ‘Good Cholesterol’

For purposes of comparison, the researchers also examined inherited variations in 13 genes that determine levels of LDL, the so-called bad cholesterol. It is well known and widely accepted that lowering LDL levels by any means — diet and exercise, statin drugs — reduces risk. Clinical trials with statins established with certainty that reducing LDL levels is protective. So, the researchers asked, did people who inherited gene variations that affected their LDL levels, have correspondingly higher or lower heart disease risk?

The study found, as expected, that gene variations that raise LDL increase risk and those that lower LDL decrease risk. The gene effects often were tiny, altering LDL levels by only a few percent. But the data, involving tens of thousands of people, clearly showed effects on risk.

Whether some benefit financially from a theory x is completely irrelevant whether that theory is valid or not. The causal link of elevated cholesterol to CHD was widely established already at the time when statin industry was non-existent.

Gina Kolata'a NYT article has the following quote: "First the investigators looked at variations in a well-known gene, endothelial lipase, that affects only HDL. About 2.6 percent of the population has a variation in that gene that raises their HDL levels by about 6 points."

"6 points" is approximately 0.155 mmol/L.

When one examines the Framingham data, it is clear that Risk Ratios are significantly lower at HDL levels >= 100 "points" i.e 2.6 mmol/L.

High HDL is a MARKER of Low Risk, it is not a Factor.

Whenever my physician suggests that I "should take a statin", "as your LDL is 3(mmol/L)", I point out the following: i) my HDL is 3 mmol/L, my TG is 0.5 mmol/L - thus my TG/HDL is in the lowest RR quintile ii) my HsCRP is 0.7 - thus the current clinical inflammation marker is also low iii) The NNT for statins 250 persons iv) I have no intention of laying myself open to "muscle weakness" v) I have no intention of interfering with my mevalonate production pathway - I could easily end up with liver damage.

The framingham algorithm is antique, and gives totally flawed risk profile, especially for young people. High SFA consumption is known to render HDL pro-inflamatory.

LDL-C = Causal Factor influencing CHD

HLD-C = Not causally related to CHD

Effect of Long-Term Exposure to Lower Low-Density Lipoprotein Cholesterol Beginning Early in Life on the Risk of Coronary Heart Disease: A mendelian Randomization Analysis

"Background LDL-C is causally related to the risk of CHD. However, the association between long-term exposure to lower LDL-C beginning early in life and the risk of CHD has not been reliably quantified"

Conclusions Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life.

Background: High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal .

Interpretation: Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction.

Prevention of heart disease: LDL reduction is the outcome of choice? Absolutely yes.

"There is only one well-established relationship between blood cholesterol lipid fraction and coronary artery disease (CAD) That meets all the Heiss and Tyroler criteria of causality. While there are a number of blood lipid fraction, only LDL cholesterol satisfies These criteria"

@Peter:the current literature (2010-2012) strongly argues that a diet high in processed food alters the gut microbiota. This in turn induces a whole body inflammatory state. according to this hypothesis CHD, cancers, obesity and diabetes are simply symptoms of systemic inflammation.

Recent studies have revealed a close relationship between inflammatory and metabolic pathways, and inflammation is now recognized to have a major role in obesity and metabolic diseases such as insulin resistance and atherosclerosis. The human body is home to a large number of distinct microbial communities, with the densest population in the distal gut (the gut microbiota). Bacteria have long been known to activate inflammatory pathways, and recent data demonstrate that the gut microbiota may affect lipid metabolism and function as an environmental factor that influences the development of obesity and related diseases. Here, we review how the gut microbiota may affect metabolic diseases by activating the innate immune system.

If LDL is the end all be all of heart disease then how do you explain the fact that omega 3 supplementation reduces heart attack incidence even though it raises LDL levels (1)(2)(3)(4)

"DHA supplementation from algal oil, a marine source of (n-3) fatty acids not extracted from fish, may reduce serum TG and increase HDL-C and LDL-C in persons without coronary heart disease"

Hmmm, isn't saturated fat demonized for the same effects on HDL, triglycerides and LDL ?

The lyon diet heart study was the most successful of it's kind, it reduced heart attack incidence by 70%. Their were no differecnes in total blood cholesterol between the control and intervention group (5) although the intervention group had higher blood levels of antioxidants and omega 3's.

You like animal studies don't you peter ? So here's one especially for you.

BHT reduces athersclerosis in rabbits even though it raises LDL levels (6)

Did you also know that linoleic acid significantly reduces LDL cholesterol levels ?

Therefore according to your statemnt that "No matter what mechanism is used, lowering LDL cholesterol will results in lower rate of cardiovascular events" we should expect to see reduced cardivascular events when we replace saturated fats with omega linoleic acid. What do we see ?

A two fold increase in incidents in the sydney heart study and four fold increase in the rose corn oil trial (7) Whoooops. Oh yeah and cholesterol levels were reduced in both trials

Atherosclerotic plaque contains an unusually high amount of linoleic acid and the linoleic acid content of plaque correlates well with dietary intake (8)

"These findings imply a direct influence of dietary polyunsaturated fatty acids on aortic plaque formation and suggest that current trends favouring increased intake of polyunsaturated fatty acids should be reconsidered"

This was almost 20 years ago ...

Did you know that carotid plaque contains high levels of oxdized LDL and there is no correlation between oxidized LDL levels and total LDL levels ? (9)

Did you know that higher levles of oxidized LDL are correlated with greater heart attack risk regardless of total LDL levels (10)

"A potential causative role in atherosclerosis and heart diseasehas indeed been detected for oxidized LDL, but this form of LDLshows no correlation with serum levels of native LDL. Rather,individual antioxidant status appears to be a ke factor influencingserum concentrations of oxidized LDL" (11)

In my view 2 single facts speak against the "pleitrophic effects" of statins:

a) There exist ridiculously linear relationship between LDL-C lowering and the decrease of cardiovascular events observed in 5-year statin therapy initiated at mean age of 63. 15% reduction in LDL-C = 15% reduction in events, 45% reduction in LDL-C = 45% reduction in events, and so forth.

b ) A meta-analysis on mendelian randomized controlled trials with over 1,000,000 genotypes have shown that people with inherited LDL-C lowering mutations in the statin targeted HMG-CoA gene showed no heterogeneity between other studied SNPs with regard to the decrease in CHD risk per unit of LDL reduction, which suggests that the effects of statin to the risk of CHD is mediated largely or entirely through effect on circulating levels of LDL, rather than through some other pleiotropic effect.

@Tom

the Colpo nonsense about fish oil and LDL-C has already refuted long time ago by PrimitiveNutrition. Your premises simply don't hold water, fish oil increases LDL-C only on patients with very high triglycerides (the second video all about oxLDL):

Herbivore mammalians do get atherosclerosis to some degree in their wild habitat, and elevated cholesterol has been associated as the main correlate for this increased risk. Elevated LDL-C (LDL-C >70mg/dl) in free-ranging primates eating only foods in their natutal habitat is strongly associated with atherosclerosis in these primates. Wild primates typically have their LDL-C in the 40 to 70 range. Atherosclerosis is a disease of herbivores.

"Lower, the better" has been repeatedly proven in randomized, placebo-controlled double-blinded trials together with mendelian randomized controlled trials. The story is ended.

Just like Sydney trials showed corn oil may promote strokes (not necessarily atherosclerosis), there's also preliminary evidence that vegetable oils may cause damage to the endothelium, however this does not really refute the lipid theory, which dictates that elevated cholesterol CAUSES heart disease. The only vegetable oil I personally use very sparingly is canola oil (only 6% saturated fat content). Similarly, there's preliminary evidence that dietary cholesterol CAUSES damage to arteries independent of its effect to serum cholesterol levels. Again, this does not refute the lipid theory. Elevated serum cholesterol is associated with increase risk for atherosclerosis in every single mammalian specimen in the face of this planet (includes birds and insects).

The inflammation theory behind CHD does not have any evidence from mechanism studies and neither from studies on humans. Inflammation is a downstream, not a causal factor; people with inherited high levels of CRP do not have increased risk for atherosclerosis (correlation does not equal causation):

The Tsinamese have horrible amount of inflammation but low LDL-C cholesterol, hence no atherosclerosis.

Inflammation and Infection Do Not Promote Arterial Aging and Cardiovascular Disease Risk Factors among Lean Horticulturalistshttp://www.plosone.org/article/info:doi/10.1371/journal.pone.0006590

BTW elevated cholesterol levels in young people and in midlife has not only been associated with risk of CHD but also with Alzheimer, prostate cancer and impotence also in high-risk Western cohorts where LDL-C levels +200% above to what is biologically normal is the norm, thus weakening the statistical power.

Passwater:, Is it accurate to say that only oxidized-LDL starts the plaque process?

Steinberg: No, it seems to me very likely that other modified forms of LDL are involved in plaque formation. What we know so far is that the use of antioxidants can decrease the rate of progression of lesions by 50-80%. That would speak to a major involvement of oxidation, but other things can also lead to foam cell formation. Studies by Dr. John C. Khoo in my laboratory have shown that aggregation of LDL with itself markedly increases the rate of uptake by macrophages. [15] The uptake in that case occurs by way of the native LDL receptor, not the acetyl LDL receptor or oxidized LDL receptor.

Studies by Drs. J. S. Frank and A. M. Fogelman at UCLA have demonstrated the generation LDL aggregates in the subendothelial space. [16] Aggregation does not depend upon prior oxidative modification. So here is a quite distinct mechanism by which LDL uptake into the macrophages can be accelerated and can perhaps initiate the fatty streak lesion.

Studies by Dr. Joseph L. Witztum and others in our laboratory have shown that minor modifications in the structure of LDL can render it immunogenic. Autoantibodies against oxidized LDL have been demonstrated in rabbits and in humans as well. Therefore, a complex of a modified LDL particle and an antibody against it can be taken up into macrophages by way of a completely different receptor, the receptor for immunoglobulins (the FC receptor).

So, there are at least two or three alternative modifications of LDL that could account for foam cell formation. These have not yet been studied in vivo as intensively as oxidative modification, and so we are not in a position to say with any confidence how important they may be.http://www.healthy.net/scr/interview.aspx?Id=197

buddies, unfortunately I cannot no longer participate in the discussion. Meanwhile, I want people to understand that in order to demonstrate the causal relationship of LDL-C cholesterol to CHD (defined as a composite of cardiovascular death, nonfatal myocardial infarction, or coronary revascularization as adopted by the CARDIoGRAM consortium) I've covered animal experiments, double-blinded, placebo controlled statin trials, surgical studies to lower LDL-C and thus CHD events through bypass of the intestine. I've covered bile-acid sequestrants, I've shown that the so-called "pleitrophic effects" of statins are plain nonsense in terms that these extra-effects are simply integral part of lipid-lowering itself. I've referred to mendelian randomized controlled trials with over million genotypes, and covered a meta-regression curve accumulated from 108 randomized controlled trials of various medical and dietary based lipid modifying interventions has established that lowering LDL cholesterol significantly decreases the risk of coronary heart disease and all-cause mortality, independent of changes to HDL cholesterol and triglycerides, and non-lipid effects of specific drugs. Furthermore, I've covered epidemiology in this Guyenet's post:

I am sure there are tons of interesting deviation or something that looks like deviation in the hands of cholesterol confusionists. However, the take home message is quality over quantity, science is not a democracy, 1 study can be more important that 100 other studies because methodological superiority. Sydney trial is absolutely nothing next to REVERSAL trial, f.ex .

Whenever you see nonsense posted by Colpo, Masterjohn and other flat earth society members keep in mind the that science is about preponderance of evidence. The cholesterol confusionist will try to use gimmick in order to sabotage and twist the truth in order to make it seem that LDL-C cholesterol +200% above to what is biologically normal is not dangerous itself. Just like the flat earth society: they try to toss every imaginable argument to confuse those who are willing to listen. In order to rationalize their appeal-to-nature fallacy and sell a diet heavy in SFA and dietary cholesterol they remain in denial about the pathophysiology of CHD. Everything goes as long as it does not include excess LDL cholesterol stucking in the intima: it's the oxLDL, it's the inflammation, it's wheat, it's the sugar, it's the obesity, it's the veggie oils, etc.

"The third characteristic is selectivity, drawing on isolated papers that challenge the dominant consensus or highlighting the flaws in the weakest papers among those that support it as a means of discrediting the entire field. An example of the former is the much-cited Lancet paper describing intestinal abnormalities in 12 children with autism, which merely suggested a possible link with immunization against measles, mumps and rubella.19 This has been used extensively by campaigners against immunization, even though 10 of the paper's 13 authors subsequently retracted the suggestion of an association.20 Fortunately, the work of the Cochrane Collaboration in promoting systematic reviews has made selective citation easier to detect.

Another is a paper published by the British Medical Journal in 2003,21 later shown to suffer from major flaws, including a failure to report competing interests,22 that concluded that exposure to tobacco smoke does not increase the risk of lung cancer and heart disease. This paper has been cited extensively by those who deny that passive smoking has any health effects, with the company Japan Tobacco International still quoting it as justification for rejecting ‘the claim that ETS is a cause of lung cancer, heart disease and chronic pulmonary diseases in non-smokers’ as late as the end of 2008.23

Denialists are usually not deterred by the extreme isolation of their theories, but rather see it as the indication of their intellectual courage against the dominant orthodoxy and the accompanying political correctness, often comparing themselves to Galileo".http://eurpub.oxfordjournals.org/content/19/1/2.full

Peter, for all the dancing around you've done-- reiterating how many times you've "demonstrated" your theory by copious block-quoting of your preferred sources -- you still haven't convincingly made your case. Of course, now you've "demonstrated" that LDL-C is the be-all/end-all, you get to refer to everything else, including criticisms undermining central tenants of that theory, as "denialism". Elsewhere, you make statements about "those laypeople new to obesity research" as though you yourself have some professional qualifications in this area.

Pray tell, what is your professional involvement with biomedical research? In particular, what gives you the professional insider knowledge to dismiss a high-profile researcher like Ron Krauss out of hand?

BTW, your quoting of Steinberg is interesting, because he himself seems to be saying that modified LDL is what is taken up to initiate foam cell formation. The self-aggregation referred to was induced by mechanical treatment in vitro (not in vivo), and therefore still counts as modification in my book.

Look, I agree that LDL-P is important, because it is the substrate for various modifications that can initiate foam cell formation. Less substrate (within reason) = less foam cell formation (probably). But this is obviously mediated by many pathways, and is contingent on the size/integrity of the LDL particle.

I'm not a researcher in this field, nor am I a genius, but it doesn't take rocket science to figure out that the relative magnitude of these other processes, and variability within LDL, could easily outweigh the simple mass measurement of LDL-C in terms of determining risk. From the papers I've seen, inflammation, antioxidant-status, and so on, are considered by *main-stream* researchers to be important aspects of the atherosclerotic process. I suggest that you are persistently misrepresenting this aspect of the field.

As you say "buddies, unfortunately I cannot no longer participate in the discussion." But as Blake said, "opposition is true friendship", so I thank you for stimulating me to look deeper into this area to see if I've missed something.

ok, I'll do an exception just for you. The world has learned about oxLDL pretty much from Daniel Steinberg. Steinberg advocates a low-fat diet that result in very low LDL-C levels. The discordance between LDL-P and LDL-C is pretty much seen only with people who have metabolic syndrome. Again, skeptics miss the overall picture, which scientists like Daniel Steinberg try to convey;

Evidence Mandating Earlier and More Aggressive Treatment of Hypercholesterolemia

"One important line of evidence comes from a consideration of the Japanese experience. In 1952, mortality from CHD among Japanese men 55 to 64 years of age was <10% of what it was in the United States.15,16 Their total cholesterol levels at the time averaged ≈160 mg/dL (estimated LDL, ≈80 mg/dL). It is noteworthy that the Japanese enjoyed this relative immunity to CHD despite the fact that the prevalence of one of the major risk factors—cigarette smoking—was much higher in Japan than in Western countries,17 and another—-hypertension—was just as high.18 Even the diabetic population in Japan fares better than the diabetic population in Western countries. In 1985, almost 30% of British male diabetics but only ≈15% of the Japanese male diabetics had CHD.19 The implication is that if blood cholesterol levels are sufficiently low, the other dominant risk factors, including cigarette smoking, hypertension, and diabetes mellitus, constitute much less of a threat".http://circ.ahajournals.org/content/118/6/672.full

“All lipoprotein particles in the LDL fraction are atherogenic, independent of size”

http://www.lipid.org/uploads/300/Expert%20Panel%20Paper.pdf

LDL-P, oxLDL, etc are abused in online by the cholesterol confusionist in order to make the big picture very blurry and confused. This is what merchants of doubt do. To trick lay people, they aim to sabotage, confuse and distort an issue where scientific consensus is exceptionally strong:

The Cause of Atheroclerosis (W. Roberts, editor-in-chieg, American Journal of Cardiology)

"In summary, the connection between cholesterol elevation and atherosclerotic plaques is clear and well established. Atherosclerosis is a cholesterol problem! If one has elevated cholesterol, has an elevated blood pressure, smokes cigarettes, or has an elevated blood sugar, these additional factors serve to amplify the cholesterol damage but they by themselves do not produce atherosclerotic plaques! Societies with a high frequency of systemic hypertension or a high frequency of cigarette smoking but low cholesterol levels rarely get atherosclerosis".

Thus, although not clearly established at this time, to prevent atherosclerotic plaques, the serum LDL cholesterol must be <70 mg/dL, the serum total cholesterol certainly <150 mg/dL, and the high-density lipoprotein (HDL) cholesterol >20 mg/dL. The latter—surely a surprise to most readers—is in patients with a serum total cholesterol level about 130 mg/dL and a LDL cholesterol level of about 60 mg/dL. Exactly what HDL cholesterol level is required to prevent plaques is unclear at this time, but clearly if the LDL cholesterol is very low (eg, 50 mg/dL), then a low HDL cholesterol—as long as it is >20 mg/dL—appears not to be dangerous. Ideal may be equal serum HDL and LDL cholesterol levels or an HDL cholesterol > LDL cholesterol.In summary, the recommended guideline numbers—particularly those for primary prevention—are intended for decreasing the risk of atherosclerosis events, not for preventing formation of atherosclerotic plaques"http://ncp.sagepub.com/content/23/5/464.full

“The molecular basis for the effects of dietary saturated fat on plasma LDL cholesterol levels is well understood. Saturated fat influences the LDL receptor activity of liver cells as described by Brown and Goldstein, dietary saturated fat suppresses messanger RNA synthesis for the LDL receptor. This decreases hepatic LDL receptor activity and slows the removal of LDL from the blood, thus increasing the concentration of LDL cholesterol in the blood. Dietary cholesterol augments the effects of saturated fat further suppressing the hepatic LDL receptor activity and raising the plasma LDL cholesterol levels”.

"Several lines of evidence suggest that plasma levels of LDL-cholesterol in the range of 25-60 mg/dl (total plasma cholesterol of 110 to 150 mg/dl) might indeed be physiologic for human beings. First, in other mammalian species that do not develop atherosclerosis, the plasma LDL-cholesterol level is generally less than 80 mg/dl. In these animals the affinity of the LDL receptor for their own LDL is roughly the same as the affinity of the human LDL receptor for human LDL, implying that these species are designed by evolution to have similar plasma LDL levels. Second, the LDL level in newborn humans is approximately 30 mg/dl, well within the range that seems to be appropriate for receptor binding. Third, when humans are raised on a low fat diet, the plasma LDL-cholesterol tends to stay in the range of 50 to 80 mg/dl. It only reaches levels above 100 mg/dl in individuals who consume a diet rich in saturated animal fats and cholesterol that is customarily ingested in Western societies".

Thanx for ur post and giving us a hugefull information, i also read somewhere The omega-3 fatty acids found in Fish Oil possesses many health benefits.and recomended by many Health Autorities as a part of Balanced Diet. Fish Oil contains Omega-3 Fatty Acids, specifically Docosahexaenoic Acid (DHA) and Eicosapentaenoic Acid (EPA). One of the Health Benefits linked to Fish Oil is a low risk of Heart Attack. very healpfull for Blood Circulations. is this true..????

About Me

I'm an obesity researcher, neurobiologist, and author. In addition to my research, I enjoy synthesizing and communicating science for a general audience. I have a BS in biochemistry (University of Virginia) and a PhD in neurobiology (University of Washington).
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